9M8V

dimer-GPR3-Gs complex

This is a non-PDB format compatible entry.

Summary for 9M8V

• Entry DOI: 10.2210/pdb9m8v/pdb
• EMDB information: 63723
• Descriptor: Soluble cytochrome b562,G-protein coupled receptor 3, Isoform Gnas-2 of Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, ... (7 entities in total)
• Functional Keywords: gpcr, dimer, g-protein complex, membrane protein
• Biological source: Escherichia coli; More
• Total number of polymer chains: 5
• Total formula weight: 192400.10

Authors

Geng, C.,Jun, X. (deposition date: 2025-03-13, release date: 2025-09-24, Last modification date: 2025-10-01)

Primary citation

Chen, G.,Blahova, J.,Staffen, N.,Hubner, H.,Nunhofer, N.,Qiu, C.,Gmeiner, P.,Weikert, D.,Du, Y.,Xu, J.
Mechanism and function of GPR3 regulated by a negative allosteric modulator.
Nat Commun, 16:7988-7988, 2025

PubMed Abstract: Allosteric modulators have gained substantial interest in current GPCR drug discovery. Here, we present a mechanism of allosteric modulation involving the dimerization of GPR3, a promising drug target for metabolic diseases and central nervous system disorders. We show that GPR3 forms constitutive homodimers in live cells and reveal that the inhibitor AF64394 functions as a negative allosteric modulator (NAM) specifically targeting dimeric GPR3. Using cryogenic electron microscopy (cryo-EM), we determine the structures of the AF64394-bound GPR3 dimer and its dimer-Gs signaling complex. These high-resolution structures reveal that AF64394 binds to the transmembrane dimer interface. AF64394 binding prevents the dissociation of the GPR3 dimer upon engagement with Gs and restrains transmembrane helix 5 in an inactive-like intermediate conformation, leading to reduced coupling with Gs. Our studies unveil a mechanism of dimer-specific inhibition of signaling with significant implications for the discovery of drugs targeting GPCRs capable of dimerization.

PubMed: 40866348
DOI: 10.1038/s41467-025-63422-1

Experimental method

ELECTRON MICROSCOPY (3.83 Å)